Prolonged oxygen deprivation is a common clinical condition and may render victims vulnerable to a variety of neurological disorders. However, there is little known about membrane properties, especially neuronal excitability in prolonged hypoxia during development. Previous work from this laboratory has suggested that chronic hypoxia causes cortical dysfunction, rendering immature neurons more excitable and susceptible to subsequent stress than naive neurons via Na+ channel dysregulation. Recent studies further suggest that cortical delta-opioid receptors (DOR) play a protective role in neuronal response to hypoxic stress. DOR activation protects cortical neurons from neuroexcitotoxicity and hypoxic insults via differential regulation of MAP kinase subtypes. Chronic hypoxia decreases DOR expression in the cortex, while DOR up-expression potentiates ionic homeostasis in the cortex under hypoxia. The general hypothesis of this project is that hypoxic impairment of DOR expression may contribute to cortical dysfunction via Na+ channel dysregulation, while electro-acupuncture induced upregulation of the DOR system is a therapeutic strategy against hypoxic injury and dysfunction in the cortex. Using electrophysiological, transgenic and molecular approaches, this project will accomplish three specific aims: 1) to determine if DOR up-expression protects from hypoxic dysregulation of cortical excitability; 2) to determine if DOR protection is dependent on alterations in Na+ channel expression and/or function; and 3) to determine if electro-acupuncture induces DOR expression and alleviates the hypoxic dysfunction via MAP kinases. The outcome of this proposal will improve the understanding of neuronal dysfunction resulting from hypoxic stress and provide clues to develop novel and alternative solutions for hypoxic/ischemic insults to the brain.